The different areas of the areas from medulla, pons, mesencephalon and diencephalon are very important as to maintenance of wakefulness or sleep. The areas between the medullary area up to the diencephalon is where the neurotransmitters are going to be found or produce. These neurotransmitters are the ones involved with sleep-wake cycles.

The parts of the brain that have to do with sleep are called SOMNOGENIC CENTER OR SYSTEMS. The hypothalamus, medulla, thalamus, basal forebrain and the pineal gland are part of these.

Basal Forebrain

This exhibits changes in adenosine levels that increase with wakefulness and decrease with sleep. This is very important in sleep initiation. When adenosine levels increase, you have a patient that is more awake and when it decrease, you have a patient who will now go to sleep. Adenosine receptors in this region may mediate caffeine's alerting effects as an antagonist on these receptors.

Adenosine (ADO) is a purine nucleoside comprising a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a β-N9-glycosidic bond. Adenosine plays an important role in biochemical processes, such as energy transfer—as adenosine triphosphate (ATP) and adenosine diphosphate (ADP)—as well as in signal transduction as cyclic adenosine monophosphate, cAMP. It is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal, with levels increasing in the brain with each hour an organism is awake.

The different adenosine receptor subtypes (A1, A2A, A2B, and A3) are all seven transmembrane spanning G-protein coupled receptors. These four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. The A2A and A2B receptors couple to Gs and mediate the stimulation of adenylate cyclase, while the A1 and A3 adenosine receptors couple to Gi which inhibits adenylate cyclase activity. Additionally, A1 receptors couple to Go, which has been reported to mediate adenosine inhibition of Ca2+ conductance, whereas A2B and A3 receptors also couple to Gq and stimulate phospholipase activity. 

Thalamus

The reticular nucleus sends GABAergic projections to other thalamic nuclei, suppressing these nuclei and inhibiting the excitation of the cortex. This causes the individual to become drowsy and fall asleep. Not all nucleus of the thalamus is involved in sleep. Some has to do with wakefulness.

Gamma-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is also directly responsible for the regulation of muscle tone. Although chemically it is an amino acid, GABA is rarely referred to as such in the scientific or medical communities, because the term "amino acid," used without a qualifier, conventionally refers to the alpha amino acids, which GABA is not, nor is it ever incorporated into a protein. In spastic diplegia in humans, GABA absorption becomes impaired by nerves damaged from the condition's upper motor neuron lesion, which leads to hypertonia of the muscles signaled by those nerves that can no longer absorb GABA.

Hypothalamus

Here, the ventro-lateral preoptic nucleus (VLPO) produces GABA and Galanin which are inhibitory and are projected to the arousing centers of the brain thus inhibiting wakefulness. The ventral anterior region specifically the suprachiasmatic nucleus (SCN) controls the circadian rhythm.

Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors. The functional role of galanin remains largely unknown; however, galanin is predominately involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor. Galanin is linked to a number of diseases including Alzheimer's disease, epilepsy as well as depression, eating disorders and cancer. Galanin appears to have neuroprotective activity as its biosynthesis is increased 2-10 fold upon axotomy in the peripheral nervous system as well as when seizure activity occurs in the brain. It may also promote neurogenesis. Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide and as such inhibits neurotransmitter release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine, serotonin, and norepinephrine, and also with other neuromodulators such as neuropeptide Y, substance P, and vasoactive intestinal peptide.

Pineal Gland

This produces melatonin from serotonin and begins releasing it during the evening, with a peak at 3-5 am. This may act to fix sleep-wake behaviors with the light-dark cycle. The melatonin cycle is regulated by projections from the suprachiasmatic nucleus and sympathetic afferents from the superior cervical ganglia.

Melatonin is a naturally occurring compound found in animals, plants, and microbes. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA.

Serotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal (GI) tract, platelets, and in the central nervous system (CNS) of animals including humans. It is popularly thought to be a contributor to feelings of well-being and happiness. Approximately 90% of the human body's total serotonin is located in the enterochromaffin cells in the alimentary canal (gut), where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions. These include the regulation of mood, appetite, and sleep. Serotonin also has some cognitive functions, including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants. Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing. Serotonin is mainly metabolized to 5-HIAA, chiefly by the liver. Metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative. The latter is then excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonin's growth-promoting effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.

Medulla

In the dorsolateral region of medullary reticular formation and anterior solitary tract nucleus, transmitters that has to do with the NON-REM sleep are found. These areas also synchronize EEG and may induce non-REM sleep. Also trigger atonia prior to the onset of REM sleep via projections to nucleus gigantocellularis of the medullary reticular formatio that forms the lateral reticulospinal tract. The reticulospinal tract keeps you in a state of hypotonia during REM sleep. Nucleus reticularis pontis may trigger REM sleep via projections to mesencephalic ARAS nuclei.

Summary

NEUROTRANSMITTERS FOR SLEEP

Norepinephrine is a catecholamine with multiple roles including as a hormone and a neurotransmitter. Areas of the body that produce or are affected by norepinephrine are described as noradrenergic. One of the most important functions of norepinephrine is its role as the neurotransmitter released from the sympathetic neurons affecting the heart. An increase in norepinephrine from the sympathetic nervous system increases the rate of contractions. As a stress hormone, norepinephrine affects parts of the brain, such as the amygdala, where attention and responses are controlled. Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. It increases the brain's oxygen supply. Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus coeruleus. When norepinephrine acts as a drug, it increases blood pressure by increasing vascular tone (tension of vascular smooth muscle) through α-adrenergic receptor activation; a reflex bradycardia homeostatic baroreflex is overcome by a compensatory reflex preventing an otherwise inevitable drop in heart rate to maintain blood pressure. Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase in the secretory granules of the medullary chromaffin cells. It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system, where it is released from noradrenergic neurons in the locus coeruleus. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

See More information on Serotonin above.

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.

PATHWAYS INVOLVED IN SLEEP

There are two brainstem circuits important for sleep regulation. One is the pathway for NON-REM sleep and the other is for REM sleep.

Non-REM Sleep

GABA is produced at the area of hypothalamus and suppresses all areas of the brain that have to do with wakefulness. Cortical neurons tend to discharge in synchronized bursts during NREM sleep and in non-synchronized bursts in the wakeful state.

REM Sleep

In the brainstem, particularly at the upper pons, there are cells that will produce GABA and Galanin. This will then initiate the REM stage of sleep. In REM sleep, the EEG is generally asynchonous as well. Most complex visual dreaming has been found to occur in the REM period.

AROUSING SYSTEMS

These are areas that have to do with wakefulness. Such areas are the mesencephalon (includes the ascending reticular activating system or ARAS), hypothalamus, basal forebrain and thalamus.

It is at this area that the Ascending Reticular Activating System (ARAS) is found. The ARAS is the most  important of the arousing systems. The ARAS goes all the way from the medulla, pons, the area of the mesencephalon and then into the area of the diencephalon. This is important as far as wakefulness is concerned. The ARAS also includes noradrenergic locus ceruleus and the serotonergic raphe nuclei.

ARAS → Medulla → Pons → Mesencephalon → Diencephalon

Aside from the ARAS, the ventral tegmental area of the mesencephalon and the mesencephalic raphe nuclei are involved. The Ventral tegmental area of the mesencephalon (periaqueductal gray) will produce dopamine (dopaminergic) and the mesencephalic raphe nuclei will produce serotonin (serotonergic)

Dopamine, a simple organic chemical in the catecholamine family, is a monoamine neurotransmitter and hormone, which has a number of important physiological roles in the bodies of animals. In addition to being a catecholamine and a monoamine, dopamine may be classified as a substituted phenethylamine. Its name derives from its chemical structure, which consists of an amine group (NH2) linked to a catechol structure, called dihydroxyphenethylamine, the decarboxylated form of dihydroxyphenylalanine (acronym DOPA). In the brain, dopamine functions as a neurotransmitter—a chemical released by nerve cells to send signals to other nerve cells. The human brain uses five known types of dopamine receptors, labeled D1, D2, D3, D4, and D5. Dopamine is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area.

For more information on Serotonin. See above.

Summary of Important Nuclei

PATHWAYS INVOLVED IN WAKEFULNESS

There are 5 Projection system involved in wakefulness. These are the following: Cholinergic projection system, Dopaminergic projection system, Noradrenergic projection system, Serotonergic projection system and Histaminergic projection system.

Cholinergic Projection System

Pedunculopontine group of nuclei, lateral dorsal degmental group → Acetylcholine → Wakefulness

Basalis of Meynert (Basal forebrain) → Acetylcholine → Wakefulness

Dopaminergic Projection System

Midbrain → Dopamine → Area of the Frontal Cortex stimulated → Maintains Wakefulness

Noradrenergic Projection System

Locus ceruleus (upper pons) and lateral tegmental nuclei (lower pons) → Norepinephrine →  Pontomedullary nuclei → Olives → Wakefulness

Serotonergic Projection System

Dorsal (mesencephalic) raphe nuclei → Serotonin → Cortex → Wakefulness

Histaminergic Projection System

Tuberomamillary nucleus of the hypothalamus → Histamine → Mamillothalamic pathway → Thalamocortical pathway → Cortex → Wakefulness 

AWAKE-AROUSAL SYSTEMS

All neurotransmitters from the pons and midbrain has to go go up through brainstem reticular formation and pass to the basal forebrain bundle while some pass through nonspecific thalamic nuclei and these stimulates the cortex for wakefulness. Independently, histaminergic projections from the posterior hypothalamus as well as orexin or hypocretin from lateral or posterolateral hypothalamus also goes up to maintain wakefulness.

Awake State

Wakefulness is maintained mostly by the neurotransmitters hypocretin or orexin, which stimulate monoaminergic neurons. This then stimulate the cortex through the thalamus. They also suppress the ventrolateral posterior part of the hypothalamus (VLPO), which is GABAergic, producing less GABA therefore leading to wakefulness.

Sleep State

More GABAergic neurons are activated, when you're asleep. This suppresses orexin or hypocretin and monoaminergic neurons, thus inducing sleep.

CIRCADIAN RHYTHM

This is the sleep-wake cycle. It is regulated by a biological clock located in the suprachiasmatic nucleus (SCN) in the hypothalamus. Responsive to the amount of light in the environment (not artificial light). This affects melatonin release. When the SCN is activated, the person will be in a sleep state and when it is less activated, a person will be on the awake state. There are two processes involved on how an individual go from wakefulness to sleep. These are the sleep load or the homeostatic process and the alerting signal. 

When the sun is high, as the day goes on, the alerting signal or system goes up and the sleep load also rises. Since both are increasing, there has to be a more alerting system than sleep load in order for an individual to maintain wakefulness. During the night, alert level is less, so even if sleep load goes down, alerting level goes down even more causing the patient to go to sleep and to maintain sleep/ The cycle begins again the next day.

Suprachiasmatic Nucleus/Sleep Switch Interaction

When the sun goes down and external environmental light decreases, there is an increase in rhodopsin coming from the retina. There is a retino-hypothalamic tract that will bring it to the SCN. From here, there is stimulation of the pineal gland to produce melatonin. There is thus an increase in melatonin. Melatonin is brought back to the SCN where there are two melatonin receptors: one is for us to initaite sleep and the other one is to synchronize ourselves to the environment.

In the SCN, there will be a decrease in Prokineticin leading to a decrese in orexin or hypocretin production, which leads to less stimulation of tubero-mamillary nuclei. This will result to a less influence to the ventrolateral pre-optic nucleus (VLPO) of the hypothalamus leading to the production of GABA and Galanin. These neurotransmitters goes back to the SCN and is now sent to all the areas of the brain responsible for wakefulness and suppress it. This causes the individual to fall asleep.

As the sun goes up, there will be less stimulation in the SCN causing a decrease in melatonin production, which increase Prokineticin. This leads to an increase in the production of orexin and hypocretin hence more damping and inhibition of the VLPO nucleus, which produced less GABA and Galanin. With this, the individual is awake.

The cycle repeats again for another 24 hours.

REFERENCES